ABSTRACT Parent Study. This application is being submitted to PA-18-591 in accordance with NOT-AG-20-008. The proposed project builds on the parent study (R21DC017804; 2019-2022) to add new questions regarding aging. The overarching goal of the parent study is to define the language phenotype associated with the FMR1 premutation genotype. The parent study specific aims are to identify aspects of language that distinguish premutation carriers from controls; investigate the interplay between language and executive aspects of the FMR1 premutation phenotype; and explore associations with FMR1 gene dysfunction. Overview. Over 1 million individuals in the US (1:151 females, 1:468 males) carry a premutation allele on the FMR1 gene. Despite the high prevalence of the FMR1 premutation genotype, its clinical phenotype is poorly defined. Until recently, it was mistakenly believed that carriers of the FMR1 premutation were ?silent carriers? who suffered no clinical effects besides the risk of passing the mutated gene to their offspring, which could cause fragile X syndrome. However, it is now clear that premutation carriers experience a range of language, cognitive, and psychiatric symptoms. Additionally, about 10% of female carriers will develop FXTAS, a late- onset neurodegenerative disorder that is characterized, in part, by dementia, executive deficits, and cognitive decline. These clinical manifestations of the premutation are associated with reduced quality of life?both for the premutation carrier mother as well as for her children with fragile X. New, emerging evidence suggests premutation carrier mothers may experience premature age-related decline, where subtle cognitive deficits are evident in the third decade of life and appear to worsen across middle age. This is significant because it suggests that premutation carrier mothers may experience symptom aggravation at a time when caregiving burden is at its peak. Yet, there remain large gaps in our understanding of the aging cognitive phenotype. First, our current understanding is limited to a few reports that were narrowly focused on specific executive skills without broader characterization of other cognitive domains, such as language. Additionally, most prior studies have focused on mothers younger than the age of 55, which has resulted in poor understanding of symptom expression in late midlife and early old age. These knowledge gaps represent substantial barriers to effective clinical management, as we lack the data needed to understand the long-term effects of the FMR1 premutation genotype. Supplement Aims. In other forms of pathological aging, such as in dementia, subtle cognitive-linguistic deficits are observed early in disease progression, sometimes before impairments in other cognitive skills can be detected. In this Supplement we will extend this work to the study of premutation carrier mothers through the characterization of aging cognitive-linguistic deficits. This approach may provide insight into the earliest manifestations of pathological aging in this group. We aim to characterize age-related changes in cognitive- linguistic skills that may differentiate premutation carrier mothers from control mothers (Aim 1), and to determine the interplay between executive deficits, FMR1 genetic variation, and aging cognitive-linguistic skills (Aims 2 & 3). We will accomplish this goal by extending the age of the parent study sample to include new recruitment of an older cohort. This will provide us with a well-powered participant sample with representation across 35-75 years of age, allowing us to address new questions regarding age effects occurring across midlife and early old age. The proposed work will substantially contribute to understanding of aging cognitive phenotypes linked with the FMR1 premutation. This work will inform individualized risk factors (e.g., age, FMR1 CGG size) that can assist in applying a personalized medicine approach to predicting risk and implementing preventive measures. Relevance to Alzheimer?s and Related Dementias. Age is the most significant risk factor for the development of dementia-related disorders and, thus, studies of cognitive decline in aging have been identified by the NIA as falling within the Alzheimer?s Disease category. The most significant impact of this Supplement will be illuminating the FMR1 premutation genotype as a factor associated with age-related cognitive decline. The promise of this line of investigation is highlighted by recent molecular-genetic studies showing that FMR1 protein plays a critical role in regulating signaling pathways that contribute to the pathogenesis of Alzheimer?s disease and other related neurodegenerative disorders. Over one million individuals in the US are genetic carriers of the FMR1 premutation. Thus, the proposed work has broad implications for improving population health through the identification of genetic risk factors associated with pathological aging. Stimulating Future Work. This Supplement will provide a foundation for a subsequent R01 focused on the longitudinal characterization of aging neurodegenerative symptoms in the FMR1 premutation. Thus, this Supplement will be key in providing a mechanism for the PI to begin to add new questions regarding aging and neurodegeneration into her program of research. Data generated will result in an anticipated 5+ papers and 7+ presentations. The PI?s lab also includes a number of graduate and postdoctoral trainees who are interested in research careers and will be introduced to Alzheimer?s and dementia-related research through this work.